The enzyme dipeptidyl peptidase-IV (DPP-IV) inactivates a variety of bioactive peptides, including glucagon-like peptide-1 (GLP-1) and growth hormone releasing hormone (GHRH). Inhibiting DPP-IV in order to increase circulating GLP-1 is of interest as a treatment for Type II diabetes. Inactivation of DPP-IV may also increase circulating GHRH, potentially enhancing growth in domestic animals 8-(2-Aminoethylsulfanyl)-1,3,7-trimethyl-3,7-dihydropurine-2,6-dione has been described in the literature. This compound acts on the central nervous system (J. Med. Chem. (1966), 9 500-6). Inhibition of DPP-IV increases the circulating half-life of the incretin hormones GLP-1 and GIP, improving glucose tolerance in Type II diabetics. Complete inhibition of DPP-IV does not appear to be necessary: 2- to 3-fold increases in plasma concentrations of GLP-1 have been achieved in mice with inactivation of 84% to 96% of plasma DPP-IV Thus, there has been much interest in developing DPP-IV inhibitors for the treatment of Type II diabetes
DPP-IV exists as both a membrane-spanning form present in cells throughout the body and a soluble circulating form. Both forms of DPP-IV have identical enzymatic activity and cleave a wide range of bioactive peptides in vitro, including hormones, neuropeptides, and chemokines. One potential regulatory role of DPP-IV is the inactivation of GHRH through cleavage of the active form, GHRH(1-44)-NH2, to the N-terminally shortened inactive form, GHRH(3-44)-NH2, While trypsin-like degradation of GHRH also occurs, in vitro studies using GHRH analogs designed to resist cleavage at the N-terminus have demonstrated that the primary degradation of GHRH is via DPP-IV. Substitution of Ala2 with Dali prevents DPP-IV proteolysis and administration of this analog increases GH release in swine up to 2-fold. The His1, Val2 analog of GHRH is also not degraded by DPP-IV in vitro, and it demonstrates increased plasma stability over native GHRH. GHRH analogs containing the His1, Val2 substitutions were 5.4- to 12.5-fold more potent than native GHRH in release of GH in swine. Thus, inhibition of DPP-IV in vivo may increase endogenous concentrations of GHRH and enhance GH secretion.
The present invention is based on the object of providing compounds which display a therapeutically utilizable blood glucose-lowering effect. -(2-Aminoethylsulfanyl)-1,3,7-trimethyl-3,7-dihydropurine-2,6-dione has been described in the literature. This compound is also known to act on the central nervous system (J. Med. Chem. (1966), 9 500-6).